Podoplanin (Pdpn) is a type 1 transmembrane mucin-type O-glycoprotein [1, 2]. It consists of 172 amino acids in mice and 163 amino acids in humans. It is expressed in lymphatic endothelial cells (LECs) as well as many other cell types including alveolar type I epithelial cells, podocytes, osteoblast cells, and several tumor cell types [1-4]. Hence, it is also known as Tia, OTS-8, gp36 and Aggrus, based on the cell type in which it has been identified [2, 5-8]. Pdpn has an extracellular domain, a single transmembrane domain, and a short cytoplasmic tail (Fig. 1 A). It is highly conserved between rodents and humans (Fig. 1 A). Protein homology is particularly evident in the cytoplasmic carboxy-terminal tail of Pdpn, suggesting important functions. Indeed, the cytoplasmic domain of Pdpn has been shown to interact with members ofthe ERM (ezrin, radixin, moesin) proteins in epithelial cells, and to subsequently activate RhoA and promote cell transdifferentiation [9]. A striking feature of the extracellular domain of Pdpn is a high content of serine and threonine residues that could potentially be O-glycosylated [10,11] (Fig. IA). Mucin-type O-glycosylation is a prevalent form of post-translational modification of membrane and secreted proteins [12-15]. It occurs in the Golgi apparatus via sequential reactions catalyzed by specific glycosyltransferases (Fig. IB). The core of all mucin-type O-glycans is serine/threonine-linked Nacetylgalactosamine (GalNAcal-Ser/Thr), also known as Tn antigen, which is normally further modified to form distinct subtypes of Oglycans. Among them, core 1 O-glycans are a predominant form. Core 1 O-glycans are synthesized by adding galactose (Gal) to Tn antigen, a reaction catalyzed solely by the T-synthase (core 1 synthase, Cigaltl) [13-16). Core 1 structure can be further branched to form extended core 1, core 2 structures, or can be modified by adding sialic acids. These glycans are known as core 1-derived O-glycans [15,16]. Core 1-derived O-glycans are present in most cell types, especially in epithelial cells and endothelial cells [15]. Altered O-glycosylation can affect numerous processes such as glycoprotein conformation, trafficking, sorting, or degradation [14,17,18]. Moreover, the O-glycosylation state of glycoproteins may also dictate changes in cell-cell interactions and/or cell signaling [19]. The extracellular domain of mouse Pdpn contains 24 potential sites of O-glycosylation (Fig. 1A). The molecular weight of core Pdpn protein is about 17 kDa, however, Pdpn isolated from different tissues has molecular weight ranging from 37 to 41 kDa, suggesting extensive O-glycosylation. Our recent study provides the first evidence in vivo that O-glycosylation is essential for the cell surface expression of Pdpn [14], although how O-glycosylation regulates Pdpn expression/function remains to be determined. Our study also revealed a critical contribution of core 1-derived O-glycans and Pdpn to lymphatic vascular development.